Microbubbles are used as contrast agents in a variety of clinical applications, ranging from imaging, diagnostics, to therapeutics. These microbubbles are typically injected into veins to disperse in the blood stream and circulate throughout the body.
In ultrasound imaging applications, suspended microbubbles that are insonified by ultrasound pulses oscillate when the ultrasound is at a frequency near the microbubbles' resonance frequency. This oscillation causes the rapid expansion and contraction of the bubble, producing strong ultrasound echoes. Signals from the echoes increase the image contrast of the blood stream, thereby improving the visual distinction between blood and the surrounding tissues. This improvement leads to increased resolution, detection sensitivity, and accuracy of imaging, thereby facilitating enhanced detection of thrombosis and diseased tissues.
Recently, microbubbles have started to also be utilized for therapeutics. Namely, microbubbles have been applied to gene delivery and drug delivery. Further, sonoporation operations use acoustic streaming from vibrating microbubbles to produce pores on the membrane of tumor cells to lyse the cells or selectively deliver genes and/or drugs for cancer treatment.
Despite the promise of microbubble technology in a range of different biomedical applications, it remains challenging to produce monodisperse (uniform size) microbubbles. In the aforementioned applications, the microbubbles required are typically 1 to 7 μm in diameter. Conventional methods used to generate microbubbles such as sonification, high shear emulsification, inkjet printing and coaxial electrohydrodynamic atomization (CEHDA), create polydisperse (i.e. variable size) microbubbles at diameters less than 10 μm. As a result of the microbubbles' polydispersity, subsequent filtration steps are needed to attain microbubbles in a range of 1-7 μm.
While microfluidic techniques produce monodisperse (i.e. uniform size) microbubbles with excellent size-control, microfluidics generated microbubbles have lower limits of size that directly depend on the dimensions of the bubble generating microchannel orifice. Making microbubbles that are on the relevant length scale of ultrasound and therapeutics applications requires orifice widths that are less than 10 micrometers wide. Fabricating microfluidic molds with such orifice widths is expensive and requires high-resolution photolithography.
Accordingly, there is a need for new methods, systems and apparatuses for forming microbubbles with diameters of just a few micrometers.